Apoptosis, which is also called programmed cell death, is a form of cell death in which a programmed sequence of events leads to the elimination of cells without releasing harmful substances into the surrounding area. Apoptosis plays a crucial role in developing and maintaining health by eliminating old cells, unnecessary cells, and unhealthy cells. Apoptotic processes are of widespread biological significance, being involved, for example, in development, differentiation, proliferation/homeostasis, regulation and function of the immune system and in the removal of defect and therefore harmful cells. However, too little or too much apoptosis can cause many diseases. Defects in apoptosis can result in tumor, autoimmune diseases and spreading viral infections, while neurodegenerative disorders such as Alzheimer, Huntington and Parkinson diseases, AIDS and ischaemic diseases are caused or enhanced by excessive apoptosis (Fadeel B, Orrenius S, Zhivotovsky B. Apoptosis in human disease: a new skin for the old ceremony? Biochem Biophys Res Commun. 266(3), 699-717(1999)). Therefore, regulating apoptosis is important in the treatment or prevention of diseases whose pathology is related with apoptosis.
A benign tumor or malignant tumor is a group of diseases characterized by uncontrolled cell division leading to growth of abnormal tissue. Cell multiplication (proliferation) is a normal physiologic process that occurs in almost all tissues and under many circumstances, such as response to injury, immune responses, or to replace cells that have died or have been shed as a part of their lifecycle (in tissues such as skin or the mucous membranes of the digestive tract). Normally the balance between proliferation and cell death is tightly regulated to ensure the integrity of organs and tissues. The uncontrolled and often rapid proliferation of cells can lead to either a benign tumor or a malignant tumor (cancer). The unregulated growth is caused by damage to DNA, resulting in mutations to genes that encode for proteins controlling cell division.
Tumor development is a multistage process that results from the step wise acquisition of genetic alterations. These alterations may involve the dysregulation of a variety of normal cellular functions, leading to the initiation and progression of a tumor. In many tumors, pro-apoptotic proteins have inactivating mutations or the expression of anti-apoptotic proteins is upregulated, leading to the unchecked growth of the tumor and inability to respond to chemotherapy.
P53 is a pro-apoptotic gene present in all cells. P53, which is called as a tumor suppressor gene, plays a critical role in maintaining cellular homeostasis and tumor-free survival of the organism by modulating cell cycle progression or apoptosis (Vogelstein et al., Surfing the p53 network. Nature 408:307-310 (2000). Normally it induces apoptosis by activating caspases 9, 8, 7, and 3. The inactivation of p53 decreases caspase activation and therefore the cell will not undergo apoptosis. Therefore, inactivation of p53 is closely related with development of cancerous states. Mutation in the p53 gene is the most common mutation in cancer; it is present in about half of all cancer tumors, 80% in all colon cancer tumors, 50% of lung cancer tumors, and 40% of breast cancer tumors.
The tumor suppressor p53 gene is activated in response to stress stimuli and functions as a transcription factor to promote antiproliferative responses, including cell cycle checkpoint and apoptosis (Ko, L. J. & Prives, C. p53: puzzle and paradigm. Genes Dev. 10, 1054-72 (1996); Levine, A. J. p53, the cellular gatekeeper for growth and division. Cell 88, 323-331 (1997); Oren, M. Decision making by p53: life, death and cancer. Cell Death Differ. 10, 431-442 (2003); Benchimol, S. p53—an examination of sibling support in apoptosis control. Cancer Cell 6, 3-4 (2004); Harms, K., Nozell, S. & Chen, X. The common and distinct target genes of the p53 family transcription factors. Cell Mol. Life Sci. 61, 822-842 (2004)). The p53 tumor suppressor gene encodes a transcription factor that is a potent inducer of apoptosis in response to genotoxic/chemotherapeutic agents, preventing the persistence of potentially cancer-prone cells.
The p53 protein functions as a transcription factor with a high affinity for specific DNA target sequences in response to DNA damage or hypoxia. It selectively destroys stressed or abnormal cells to prevent the progression to cancer. Although the number of genes activated by p53 is rather large, the outcome of p53 activation is either cell cycle arrest in G1, in G2 or apoptosis.
Although the mechanism by which p53 activates the G1 arrest is well characterized and involves primarily the transcriptional activation of the cyclin-dependent kinase inhibitor p21Wafl, the precise nature of the p53 transcriptional program for p53-dependent apoptosis is still unclear. Among several previously identified p53 pro-apoptotic target genes, at least two pro-apoptotic members of the TNFR superfamily, Fas/Apol/CD95 and DR5/KILLER, have been shown to be regulated in a p53-dependent manner in response to genotoxic drugs (Wu, G. S. et al. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat. Genet. 17, 141-143 (1997); Owen-Schaub, L. B. et al. Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol. Cell. Biol. 15, 3032-3040 (1995); Zalcenstein, A. et al. Mutant p53 gain of function: repression of CD95(Fas/APO-1) gene expression by tumor-associated p53 mutants. Oncogene 22, 5667-5676 (2003)), suggesting a potential link between p53-mediated intrinsic pathway of apoptosis and TNF-induced extrinsic pathway of apoptosis. TNF-α is an important cytokine that orchestrates pleiotropic functions not only in the host immunity response but also in control of cell proliferation, differentiation, and apoptosis (Ashkenazi, A. & Dixit, V. M. Death receptors: signaling and modulation. Science 281, 1305-1308 (1998); Baud, V. & Karin, M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol. 11, 372-377 (2001); Chen, G. & Goeddel, D. V. TNF-R1 signaling: a beautiful pathway. Science 296, 1634-1635 (2002); Wajant, H., Pfizenmaier, K. & Scheurich, P. Tumor necrosis factor signaling. Cell Death Differ 10, 45-65 (2003); Fesik, S. W. Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 5:876-885 (2005); Rowinsky, E. K. Targeted induction of apoptosis in cancer management: the emerging role of tumor necrosis factor-related apoptosis-inducing ligand receptor activating agents. J Clin. Oncol. 23:9394-9407, (2005)). Physiologically, the secretion of TNF-α is highly localized and transient, but it is shown to be toxic. However, no clear understanding exists in the regulatory mechanisms that enable the efficient production of TNF-α or TRAIL in order to mediate its other functions such as control of cell proliferation and apoptosis.
Drugs that restore the normal apoptotic pathways have the potential for effectively treating diseases that depend on aberrations of the apoptotic pathway to stay alive and spread. Although a number of potential apoptosis inducing agents are currently being explored for cancer drug discovery, most of drugs are toxic to normal cells and show significant side effects. Therefore, a need exists to identify and develop apoptosis targets/inducers for cancer therapy.
The information disclosed in this Background of the Invention section is only for enhancement of understanding the background of the invention and therefore, unless explicitly described to the contrary, it should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art that is already known in this country to a person of ordinary skill in the art.